Abuse-proofed dosage form

ABSTRACT

A solid administration form, protected from parenteral abuse and containing at least one viscosity-increasing agent in addition to one or more active substances that have parenteral abuse potential. The agent forms, when a necessary minimum amount of an aqueous liquid is added, on the basis of an extract obtained from the administration form, a preferably injectable gel that remains visually distinct when introduced into another quantity of an aqueous liquid.

This application is a continuation of U.S. patent application Ser. No.16/032,533 filed Jul. 11, 2018, allowed, which is a continuation of U.S.patent application Ser. No. 15/587,501, filed May 5, 2017, abandoned,which is a continuation of U.S. patent application Ser. No. 15/245,424,filed Aug. 24, 2016; now U.S. Pat. No. 9,675,610; which is acontinuation of U.S. patent application Ser. No. 14/527,911, filed Oct.30, 2014, abandoned, which is a continuation of U.S. patent applicationSer. No. 14/069,439, filed Nov. 1, 2013, abandoned, which is acontinuation of U.S. patent application Ser. No. 13/803,789, filed Mar.14, 2013, abandoned, which is a continuation of U.S. patent applicationSer. No. 13/572,926, filed Aug. 13, 2012, abandoned, which is acontinuation of Ser. No. 13/365,742, filed Feb. 3, 2012, abandoned,which is a continuation of U.S. patent application Ser. No. 12/822,719,filed Jun. 24, 2010, abandoned, which is a divisional of U.S. patentapplication Ser. No. 11/007,887, filed Dec. 9, 2004, now U.S. Pat. No.7,776,314, which is a continuation-in-part of International PatentApplication No. PCT/EP2003/006314, filed Jun. 16, 2003, which claimsforeign priority benefit under 35 U.S.C. § 119 of the German PatentApplications Nos. 102 50 083.5, filed Oct. 25, 2002, and 102 27 077.5,filed Jun. 17, 2002, the entire disclosures of which patent applicationsare incorporated herein by reference.

The present invention relates to a solid dosage form with reducedparenteral abuse containing, in addition to one or more activeingredients with potential for abuse, at least one viscosity-increasingagent in quantities such that, on extraction with the assistance of anecessary minimum quantity of aqueous liquid, a gel is formed which canstill preferably pass through a needle, which gel, however, remainsvisually distinguishable even after being introduced into a furtherquantity of an aqueous liquid.

Many pharmaceutical active ingredients, in addition to having excellentactivity in their appropriate application, also have potential forabuse, i.e. they can be used by an abuser to bring about effects otherthan those intended. Opiates, for example, which are highly active incombating severe to very severe pain, are frequently used by abusers toinduce a state of narcosis or euphoria.

Dosage forms which contain active ingredients with potential for abuse,even when taken orally in an abusively large quantity, do not usuallygive rise to the result desired by the abuser, namely a rapid rush or“kick”, because blood levels of the active ingredients increase onlyslowly. In order nevertheless to achieve the desired effects and enableabuse, the corresponding dosage forms are comminuted, for exampleground, by the abuser and the active ingredient is extracted from thepowder obtained by comminution of the dosage form with the assistance ofa preferably aqueous liquid, preferably the minimum quantity necessary,and the resultant solution, optionally after filtration through cottonwool or cellulose wadding, is administered parenterally, in particularintravenously. Due to this parenteral administration, only the smallestpossible quantities of an aqueous liquid are used for extraction, inparticular so as to obtain the smallest possible injection volume withactive ingredient which results in the desired rapid rush or “kick”. Inthis manner, parenteral administration, in comparison with oraladministration, tends to give rise to an accelerated rise in levels ofthe active ingredient providing the abuser with the desired result.

In order to prevent this form of abuse, it has been proposed in U.S.Pat. No. 4,070,494 to prevent the extraction of an active ingredientfrom a dosage form by the addition of a swellable agent. On addition ofwater, this agent swells and ensures that only a small quantity ofactive ingredient containing liquid is obtained which can beadministered parenterally by the abuser. The majority of this dosageform which has swollen is cannot be administered.

A corresponding approach to the prevention of parenteral abuse alsounderlies the multilayer tablet disclosed in WO 95/20947 which containsthe active ingredient with potential for abuse and one or more gelformers each in different layers.

According to this prior art teaching, the viscosity-increasing agentsare added in quantities such that the corresponding gel cannot beadministered with the assistance of conventional hypodermic needles.

The object of the present invention was to provide a dosage form with atleast reduced potential for abuse for active ingredients having withsuch potential, which dosage form prevents any preferably still possibleparenteral, in particular intravenous, abuse of the active ingredients.

This object has been achieved by the provision of the solid dosage formaccording to the invention with at least reduced potential forparenteral abuse, which dosage form, in addition to one or more activeingredients with potential for abuse, comprises at least oneviscosity-increasing agent in a quantity such that a gel which maypreferably still pass through a needle is formed in an extract obtainedfrom the dosage form with the assistance of a necessary minimum quantityof an aqueous liquid, which gel remains visually distinguishable whenintroduced into a further quantity of an aqueous liquid.

For the purposes of the present invention, visually distinguishablemeans that the active ingredient-containing gel formed by extractionfrom the dosage form with the assistance of a necessary minimum quantityof aqueous liquid, when introduced with a hypodermic needle with adiameter of 0.9 mm into a further quantity of aqueous liquid at 37° C.,remains substantially insoluble and cohesive and cannotstraightforwardly be dispersed in such a manner that it can safely beadministered parenterally, in particular intravenously. The materialpreferably remains visually distinguishable for at least one minute,preferably for at least 10 min.

The increase in viscosity of the gel with the assistance of the selectedviscosity-increasing agent means that, although this has been renderedmore difficult, the gel may still be passed through a needle orinjected. It also means that when the resultant extract or gel isintroduced at 37° C. into a further quantity of aqueous liquid, forexample also by injection into blood, a largely cohesive thread isinitially obtained which, while it may be broken up into smallerfragments by mechanical action, it cannot be dispersed or even dissolvedin such a manner that it may safely be administered parenterally, inparticular intravenously.

Intravenous administration of such an extract would most probably resultin obstruction of blood vessels, associated with serious embolism oreven death of the abuser.

For the purposes of the present invention, an extract or gel obtainedfrom the dosage form according to the invention with the assistance of anecessary minimum quantity of an aqueous liquid, preferably water, isdeemed to be passable through a needle if the gel formed in this mannercan still be drawn up and injected back out of a hypodermic needle witha diameter of 2 mm, preferably of 1.5 mm, particularly preferably of 0.6mm. Pharmaceutical active ingredients with potential for abuse are knownto the person skilled in the art, as are the quantities thereof to beused and processes for the production thereof, and may be present in thedosage form according to the invention as such, in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof. The dosageform according to the invention is also suitable for the administrationof a plurality of active ingredients. It is preferably used for theadministration of a single active ingredient.

The present invention, thus, relates in one embodiment to a method oftreating a disease or disorder in a patient in need of such treatment,said disease or disorder being treatable with one or more activeingredients with potential for abuse, wherein said one or more activeingredients with potential for abuse are selected from the groupconsisting of opiates, opioids, tranquilizers, stimulants and narcotics,said method comprising administering to said patient the dosage formaccording to the present invention, wherein said dosage form comprisesone or more of said active ingredients effective to treat said diseaseor disorder.

The dosage form according to the invention is in particular suitable forpreventing abuse of a pharmaceutical active ingredient selected from thegroup consisting of opiates, opioids, tranquillisers, preferablybenzodiazepines, stimulants and other narcotics.

The dosage form according to the invention is very particularlypreferably suitable for preventing abuse of an opiate, opioid,tranquilliser or another narcotic, which is selected from the groupconsisting ofN-{1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide(alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine,alphaprodine,8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(alprazolam), 2-diethylaminopropiophenone (amfepramone),(±)-α-methylphenethylamine (amphetamine),2-(α-methylphenethylamino)-2-phenylacetonitrile (amphetaminil),5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine,apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine,bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one(bromazepam),2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(brotizolam),17-cyclopropylmethyl-4,5α-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),butorphanol,(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate (camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine),7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine 4-oxide(chlordiazepoxide),7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one(clonazepam), clonitazene,7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid (clorazepate),5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one(clotiazepam),10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one(cloxazolam), (−)-methyl-[3δ-benzoyloxy-2β(1αH,5αH)-tropanecarboxylate](cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol(codeine), 5-(1-cyclohexenyl)-5-ethyl barbituric acid (cyclobarbital),cyclorphan, cyprenorphine,7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(delorazepam), desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate(dextropropoxyphene), dezocine, diampromide, diamorphone,7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (diazepam),4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine),4,5α-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol,dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(dronabinol), eptazocine,8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-(a)][1,4]benzodiazepine(estazolam), ethoheptazine, ethylmethylthiambutene, ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate](ethylloflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol(ethylmorphine), etonitazene,4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), N-ethyl-3-phenyl-8,9,10-trinorboman-2-ylamine(fencamfamine), 7-[2-(α-methylphenethylamino)ethyl]-theophylline)(fenetylline), 3-(α-methylphenethylamino)propionitrile (fenproporex),N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl),7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(fludiazepam),5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one(flunitrazepam),7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(flurazepam),7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one(halazepam),10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepin-6(5H)-one(haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone(hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone(hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan,11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepine-4,7(6H)-dione(ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone(ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol (LAAM)), (−)-6-dimethylamino-4,4-diphenol-3-heptanone(levomethadone), (−)-17-methyl-3-morphinanol (levorphanol),levophenacylmorphane, lofentanil,6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1(4H)-one(loprazolam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one(lorazepam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(lormetazepam),5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol(mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine(medazepam), N-(3-chloropropyl)-α-methylphenethylamine (mefenorex),meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate),meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine(metamphetamine), (±)-6-dimethylamino-4,4-diphenol-3-heptanone(methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone),methyl [2-phenyl-2-(2-piperidyl)acetate](methylphenidate),5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital),3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopon,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine(midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil),4,5α-epoxy-17-methyl-7-morphinen-3,6α-diol (morphine), myrophine,(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)-one(nabilone), nalbuphene, nalorphine, narceine, nicomorphine,1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nimetazepam),7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam),7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nordazepam),norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),normorphine, norpipanone, the exudation from plants belonging to thespecies Papaver somniferum (opium),7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (oxazepam),(cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one(oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone(oxycodone), oxymorphone, plants and parts of plants belonging to thespecies Papaver somniferum (including the subspecies setigerum) (Papaversomniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline),1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol(pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid(pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate)(pethidine), phenadoxone, phenomorphane, phenazocine, phenoperidine,piminodine, pholcodeine, 3-methyl-2-phenylmorpholine (phenmetrazine),5-ethyl-5-phenylbarbituric acid (phenobarbital),α,α-dimethylphenethylamine (phentermine),7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one(pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradrol),1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide(piritramide),7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital),5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide(sufentanil),7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(temazepam),7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(tetrazepam), ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine, cisand trans)), tramadol,8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital),(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol and for corresponding stereoisomeric compounds, thecorresponding derivatives thereof in each case, in particular esters orethers, and the physiologically acceptable compounds thereof in eachcase, in particular the salts and solvates thereof.

The compounds(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,the physiologically acceptable compounds thereof, in particular thehydrochlorides thereof and processes for the production thereof arerespectively known, for example, from EP-A-693475 and EP-A-780369. Thecorresponding descriptions are hereby introduced as a reference and aredeemed to be part of the disclosure.

In order to verify whether a viscosity-increasing agent is suitable foruse in the dosage form according to the invention, said agent is firstformulated in a corresponding dosage form in quantities such that thereis no appreciable (±5%) influence on active ingredient release relativeto a dosage form without viscosity-increasing agent. The correspondingdosage form is moreover comminuted, preferably ground, and extractedwith 10 ml water at 25° C. If a gel is furthermore formed which meetsthe above-stated conditions, the corresponding viscosity-increasingagent is suitable for the production of a dosage form according to theinvention.

Preferably, one or more viscosity-increasing agents are used in thedosage form according to the invention, said agents being selected fromthe group consisting of microcrystalline cellulose with 11 wt. %carboxymethylcellulose sodium (Avicel® RC 591), carboxymethylcellulosesodium (Blanose®, CMC-Na C3001P®, Frimulsion BLO-5®, Tylose C300 P®),polyacrylic acid (Carbopol® 980 NF, Carbopol® 981), locust bean flour(Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), pectins, preferablyfrom citrus fruits or apples (Cesapectin® HM Medium Rapid Set), waxymaize starch (C*Gel 04201®), sodium alginate (Frimulsion ALG (E401)®),guar flour (Frimulsion BM®, Polygum 2611-75®), iota-carrageenan(Frimulsion D021®), karaya gum, gellan gum (Kelcogel F®, KelcogelLT100®), galactomannan (Meyprogat 150®), tara stone flour (Polygum4311®), propylene glycol alginate (Protanal-Ester SD-LB®), sodiumhyaluronate, tragacanth, tara gum (Vidogum SP 200®), fermentedpolysaccharide welan gum (K1A96), xanthans such as xanthan gum (Xantural180®). The names stated in brackets are the trade names by which thematerials are known commercially.

In general, a quantity of 0.1 to 25 wt. %, preferably of 0.5 to 15 wt.%, particularly preferably of 1-10 wt. % of the viscosity-increasingagent, relative to the total formulation, is sufficient in order to meetthe above-stated conditions.

The viscosity-increasing agents are preferably present in the dosageform according to the invention in quantities of 5 mg, particularlypreferably of 10 mg per dosage form, i.e. per administration unit.

In a particularly preferred embodiment of the present invention, theviscosity-increasing agents used are those which, in addition to theabove-stated conditions, also form a gel which encloses air bubbles onextraction from the dosage form with the necessary minimum quantity ofaqueous liquid. The resultant gels are distinguished by a turbidappearance, which provides the potential abuser with an additionaloptical warning and discourages him/her from administering the gelparenterally.

The active ingredient or ingredients with potential for abuse and theviscosity-increasing agents and optionally physiologically acceptableauxiliary substances may be formulated to yield the dosage formaccording to the invention in accordance with conventional methods knownto the person skilled in the art. Corresponding methods for formulatingthe dosage form according to the invention are known per se to theperson skilled in the art, for example from “Coated PharmaceuticalDosage Forms—Fundamentals, Manufacturing Techniques, BiopharmaceuticalAspects, Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann,Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, MedpharmScientific Publishers. The corresponding literature description ishereby introduced as a reference and is deemed to be part of thedisclosure.

Surprisingly, due to the inventive selection of the viscosity-increasingagents, it is possible to combine the active ingredients and theviscosity-increasing agents in the dosage form according to theinvention without spatial separation from one another, without therebeing any impairment of release of the active ingredient from thecorrectly administered dosage form relative to a corresponding dosageform which does not comprise the viscosity-increasing agent.

Obviously, however, it is also possible to combine theviscosity-increasing agents and the active ingredients in the dosageform in a mutually spatially separated arrangement.

The parenteral abuse-proofed solid dosage forms according to theinvention are preferably suitable for oral or rectal administration,particularly preferably for oral administration.

Where the dosage form according to the invention is intended for rectaladministration, it preferably assumes the form of a suppository.

If the dosage form according to the invention is intended for oraladministration, it preferably assumes the form of a tablet, a capsule orof an oral osmotic therapeutic system (OROS).

Oral osmotic therapeutic systems and suitable materials and processesfor the production thereof are known per se to the person skilled in theart, for example from U.S. Pat. Nos. 4,612,008, 4,765,989 and 4,783,337.The corresponding descriptions are hereby introduced as a reference andare deemed to be part of the disclosure.

The corresponding oral osmotic therapeutic system may preferably assumethe form of a single or twin chamber system, in each case with a singlelayer or multilayer structure. In these systems, the push layer, i.e.the layer which produces the osmotic pressure by swelling, by means ofwhich the overlying layer is expelled from the system, preferably atleast in part consists of the viscosity-increasing agents used accordingto the invention.

In a further preferred embodiment of the present invention, the orallyadministrable dosage form according to the invention assumesmultiparticulate form containing in each case the complete mixture ofactive ingredient and viscosity-increasing agent, preferably in the formof microtablets, microcapsules, micropellets, granules, spheroids, beadsor pellets, preferably packaged in capsules or press-moulded intotablets The multiparticulate forms preferably have a size in the rangefrom 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm.

The dosage form according to the invention may preferably also compriseone or more active ingredients, blended with the viscosity-increasingagent, at least in part in delayed-release form, wherein delayed releasemay be achieved with the assistance of conventional materials andprocesses known to the person skilled in the art, for example byembedding the active ingredient in a delayed-release matrix or byapplying one or more delayed-release coatings.

Delayed release of the active ingredient may preferably also be achievedby purposeful selection of one or more of the above-statedviscosity-increasing agents in suitable quantities as the matrixmaterial. The person skilled in the art may determine the agents and thequantity thereof suitable for the particular desired release by simplepreliminary testing, wherein it must, of course, be ensured that, asdescribed above, gel formation occurs when the attempt is made to abusethe resultant dosage form.

In any event, it must be ensured that the delayed-release auxiliarysubstances, and likewise further optionally present auxiliarysubstances, do not interfere with gel formation or impair the stabilityof the gel which is formed.

If the dosage form according to the invention is intended for oraladministration, it may also comprise a coating which is resistant togastric juices and dissolves as a function of the pH value of therelease environment.

By means of this coating, it is possible to ensure that, when correctlyadministered, the dosage form according to the invention passes throughthe stomach undissolved and the active ingredient is only released inthe intestines. The coating which is resistant to gastric juicespreferably dissolves at a pH value of between 5 and 7.5.

Corresponding materials and methods for the controlled release of activeingredients and for the application of coatings which are resistant togastric juices are known to the person skilled in the art, for examplefrom “Coated Pharmaceutical Dosage Forms—Fundamentals, ManufacturingTechniques, Biopharmaceutical Aspects, Test Methods and Raw Materials”by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart,1st edition, 1998, Medpharm Scientific Publishers. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

In a further preferred embodiment, the dosage form according to theinvention contains the active ingredient not only in its delayed-releaseform, but also in its non-delayed-release form. By combination with theimmediately released active ingredient, it is possible to obtain aninitial dose for rapid pain relief. The slow release from thedelayed-release form then prevents any rapid decline in action.

The invention is explained below with reference to Examples. Theseexplanations are given merely by way of example and do not restrict thegeneral concept of the invention.

EXAMPLES Example 1

Matrix tablets with the following composition per tablet

(−)-(1R,2R)-3-(3-Dimethyl- 100 mg amino-1-ethyl-2-methyl-propyl)phenolhydrochloride Hydroxypropylmethylcellulose 70 mg (Metolose 90 SH 100,000from Shinetsu), 100,000 mPa · s Xanthan, NF 10 mg Microcrystallinecellulose 123 mg (Avicel PH 102 from FMC) Highly disperse silicondioxide 4 mg Magnesium stearate 3 mg Total quantity 310 mg

were produced in the following manner in a batch size of 1000 tablets:All the constituents were weighed out and screened in Quadro Comil U10screening machine using a screen size of 0.813 mm, mixed in a containermixer (Bohle LM 40) for 15 min±15 s at a rotational speed of 20±1 rpmand pressed on a Korsch EKO eccentric press to form biconvex tabletswith a diameter of 10 mm, a radius of curvature of 8 mm and an averagetablet weight of 310 mg.

In vitro release was determined using the Ph. Eur. paddle method at 75rpm in 900 ml of pH 6.8 buffer to Ph. Eur. at 37° C., with detection byUV spectrometry, and is shown in the following Table, together with acomparison with a corresponding tablet with 80 mg ofhydroxypropylmethylcellulose (“HPMC”) without addition of xanthan.

Total quantity of active ingredient released [%] Total quantity ofactive from tablets according to ingredient released [%] Time Example 1(70 mg HPMC + from tablets with 80 mg [min] 10 mg xanthan) HPMC (withoutxanthan) 0 0 0 30 19 18 240 62 59 480 83 80 600 88 87 720 93 93

One of the tablets containing xanthan was ground and shaken with 10 mlof water. A viscous, turbid suspension formed. Once the coarse, solidcomponents of the suspension had settled out, the gel which had formedwas drawn up into a syringe with a 0.9 mm diameter needle. The drawn upgel was injected into water at 37° C. and threads, which did not mixwith the water, with the diameter of the needle remained clearlydiscernible While the threads could be broken up by stirring, they couldnot be dissolved and the thread fragments remained visible to the nakedeye. Were such an extract to be injected into blood vessels, vesselblockages would occur.

Example 2 (Comparative Example Regarding Very Poor Needle PassageProperties)

Matrix tablets with the following composition per tablet

(−)-(1R,2R)-3-(3-Dimethylamino-1- 100 mg ethyl-2-methyl-propyl)phenolhydrochloride Hydroxypropylmethylcellulose 40 mg (Metolose 90 SH 100,000from Shinetsu), 100,000 mPa · s Xanthan, NF 40 mg Microcrystallinecellulose 123 mg (Avicel PH 102 from FMC) Highly disperse silicondioxide 4 mg Magnesium stearate 3 mg Total quantity 310 mg

were produced as stated in Example 1 and their release characteristicswere investigated.

Total quantity of Time active ingredient [min] released [%] 0 0 30 19240 61 480 81 600 87 720 91

One of the tablets was ground and shaken with 10 ml of water. A viscous,turbid suspension with enclosed air bubbles formed, the viscosity ofwhich was greater than in Example 1. Once the coarse, solid componentsof the suspension had settled out, the gel which had formed was drawn upinto a syringe with a 0.9 mm diameter needle. The drawn up gel wasinjected into water at 37° C. and threads, which did not mix with thewater, with the diameter of the needle were clearly discernible. Whilethe threads could be broken up by stirring, they could not be dissolvedand the thread fragments remained visible to the naked eye. Were such agel to be injected into blood vessels, vessel blockages would occur.

Example 3

Matrix Tablets with the Following Composition Per Tablet

(−)-(1R,2R)-3-(3-dimethylamino- 100 mg 1-ethyl-2-methyl-propyl)phenolhydrochloride Xanthan, NF 80 mg Microcrystalline cellulose 123 mg(Avicel PH 102 from FMC) Highly disperse silicon dioxide 4 mg Magnesiumstearate 3 mg Total quantity 310 mg

were produced as stated in Example 1.

One of these tablets was ground and shaken with 10 ml of water. Aviscous, turbid suspension, which had enclosed air bubbles, formed, theviscosity of which was higher than in Example 1. Once the coarse, solidcomponents of the suspension had settled out, the gel which had formedwas drawn up into a syringe with a 0.9 mm diameter needle. The drawn upgel was injected into water at 37° C. and clearly discernible threads,which did not mix with the water, with the diameter of the needle werevisible. While the threads could be broken up by stirring, they couldnot be dissolved and the thread fragments remained visible to the nakedeye. Were such a gel to be injected into blood vessels, vessel blockageswould occur.

Examples 4-7

Matrix Tablets with the Following Composition Per Tablet

Example 4 5 8 7 (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl- 100 mg 100 mg100 mg 100 mg 2-methyl-propyl)phenol hydrochlorideHydroxypropylmethylcellulose (Metolose 80 mg 80 mg 80 mg 80 mg 90 SH100,000 from Shinetsu), 100,000 mPa · s Carboxymethylcellulose (TyloseC300) 10 mg Carboxymethylcellulose (Tylose C600) 10 mgHydroxyethylcellulose (Tylose H300) 10 mg Hydroxyethylcellulose (TyloseH4000) 10 mg Microcrystalline cellulose (Avicel PH 102 123 mg 123 mg 123mg 123 mg from FMC) Highly disperse silicon dioxide 4 mg 4 mg 4 mg 4 mgMagnesium stearate 3 mg 3 mg 3 mg 3 mg Total quantity 320 mg 320 mg 320mg 320 mg

were produced as stated in Example 1.

One of each of these tablets was ground and shaken with 10 ml of water.A viscous, turbid suspension with enclosed air bubbles formed. Once thecoarse, solid components of the suspension had settled out, the [gel]was drawn up into a syringe with a 0.9 mm diameter needle. The drawn upgel was injected into water at 37° C. and clearly visible threads, whichdid not mix with the water, with the diameter of the needle remaineddiscernible. While the threads could be broken up by stirring, theycould not be dissolved and the thread fragments remained visible to thenaked eye. Were such a gel to be injected into blood vessels, vesselblockages would occur.

Examples 8-13

Matrix Tablets with the Following Composition Per Tablet

Example 8 9 10 11 12 13 Morphine sulfate pentahydrate 60 mg 60 mg 60 mg60 mg 60 mg 60 mg Hydroxypropylmethylcellulose 60 mg 60 mg 60 mg 60 mg60 mg 60 mg (Metolose 90 SH 15,000 from Shinetsu), 15,000 mPa · sXanthan, NF 10 mg 30 mg Carboxymethylcellulose 10 mg (Tylose C300)Carboxymethylcellulose 10 mg (Tylose C600) Hydroxyethylcellulose (Tylose10 mg H300) Hydroxyethylcellulose (Tylose 10 mg H4000) Microcrystallinecellulose 123 mg  123 mg  123 mg  123 mg  123 mg  123 mg  (Avicel PH 102from FMC) Highly disperse silicon dioxide  4 mg  4 mg  4 mg  4 mg  4 mg 4 mg Magnesium stearate  3 mg  3 mg  3 mg  3 mg  3 mg  3 mg

One of each of these tablets was ground and shaken with 10 ml of water.A viscous, turbid suspension with enclosed air bubbles formed. Once thecoarse, solid components of the suspension had settled out, the [gel]was drawn up into a syringe with a 0.9 mm diameter needle. The drawn upgel was injected into water at 37° C. and clearly visible threads, whichdid not mix with the water, with the diameter of the needle remaineddiscernible. While the threads could be broken up by stirring, theycould not be dissolved and the thread fragments remained visible to thenaked eye. Were such a gel to be injected into blood vessels, vesselblockages would occur.

Examples 14-18

Capsules with the Following Composition of the Simple Powder Mixture PerCapsule (Size 4 Capsule)

Example 14 15 16 17 18 Morphine sulfate pentahydrate 20 mg 20 mg 20 mg20 mg 20 mg Xanthan, NF 10 mg Carboxymethylcellulose (Tylose C300) 10 mgCarboxymethylcellulose (Tylose C600) 10 mg Hydroxyethylcellulose (TyloseH300) 10 mg Hydroxyethylcellulose (Tylose H4000) 10 mg Microcrystallinecellulose (Avicel PH 102 68 mg 68 mg 68 mg 68 mg 68 mg from FMC) Highlydisperse silicon dioxide 1 mg 1 mg 1 mg 1 mg 1 mg Magnesium stearate 1mg 1 mg 1 mg 1 mg 1 mg

One of each of these tablets was ground and shaken with 10 ml of water.A viscous, turbid suspension with enclosed air bubbles formed. Once thecoarse, solid components of the suspension had settled out, the [gel]was drawn up into a syringe with a 0.9 mm diameter needle. The drawn upgel was injected into water at 37° C. and clearly visible threads, whichdid not mix with the water, with the diameter of the needle remaineddiscernible. While the threads could be broken up by stirring, theycould not be dissolved and the thread fragments remained visible to thenaked eye. Were such a gel to be injected into blood vessels, vesselblockages would occur.

1. A solid dosage form for oral administration with reduced potentialfor parenteral abuse, said dosage form comprising: (a) one or moreactive ingredients having potential for abuse selected from the groupconsisting of hydrocodone, morphine, oxycodone, tramadol, andpharmaceutically acceptable salts and solvates thereof; and (b) at leastone viscosity-increasing agent in a quantity such that an aqueousextract of a total content of the dosage form when comminuted andcombined with 10 ml of water at 25° C. forms a gel that can be drawn upinto and injected back out of a hypodermic needle having a diameter of0.9 mm, into a further quantity of water, wherein threads of the gelinjected from said needle remain visible to the naked eye in saidfurther quantity of water at 37° C.
 2. The dosage form according toclaim 1, wherein the active ingredient is oxycodone or a salt or solvatethereof.
 3. The dosage form according to claim 1, wherein the activeingredient is hydrocodone or a salt or solvate thereof.
 4. The dosageform according to claim 1, wherein the active ingredient is morphine ora salt or solvate thereof.
 5. The dosage form according to claim 1,comprising one or more viscosity-increasing agents selected from thegroup consisting of microcrystalline cellulose with 11 wt. %carboxymethylcellulose sodium, carboxymethylcellulose sodium,polyacrylic acid, locust bean flour, citrus pectin, waxy maize starch,sodium alginate, guar flour, iota-carrageenan, karaya gum, gellan gum,galactomannan, tara stone flour, propylene glycol alginate, applepectin, lemon peel pectin, sodium hyaluronate, tragacanth, tara gum,fermented polysaccharide welan gum and xanthan gum.
 6. The dosage formaccording to claim 1, in particulate form.
 7. The dosage form accordingto claim 1, comprising at least one active ingredient in controlledrelease form.
 8. The dosage form according to claim 1, comprising acoating resistant to gastric juices.
 9. The dosage form according toclaim 1, in multiparticulate form, wherein said multiparticulate form isin the form of microtablets, microcapsules, micropellets, granules,spheroids, beads or pellets, packaged in capsules or press-molded intotablets.
 10. The dosage form according to claim 1, wherein said threadsremain visible to the naked eye in said further quantity of water for atleast one minute.
 11. The dosage form according to claim 1, wherein saidthreads remain visible to the naked eye in said further quantity ofwater for at least ten minutes.
 12. The dosage form according to claim1, which further comprises microcrystalline cellulose.
 13. The dosageform according to claim 1, which further compriseshydroxypropylmethylcellulose.
 14. A solid dosage form for oraladministration with reduced potential for parenteral abuse, said dosageform comprising: (a) one or more active ingredients having potential forabuse selected from the group consisting of hydrocodone, morphine,oxycodone, tramadol, and pharmaceutically acceptable salts and solvatesthereof; and (b) one or more components having at least aviscosity-increasing influence, in a total quantity, for all saidcomponents combined, that is equal to or greater than 5 mg per dosageform, that quantity being selected such that an aqueous extract of atotal content of the dosage form, when comminuted and combined with 10ml of water at 25° C., forms a gel that is capable of being drawn intoand then expelled from a hypodermic needle having a diameter of 0.9 mm,wherein threads of said gel, formed upon exit from said needle into afurther quantity of water at 37° C., remain substantially coherent andvisible to the naked eye.
 15. The dosage form according to claim 14,wherein the active ingredient is oxycodone or a salt or solvate thereof.16. The dosage form according to claim 14, wherein the active ingredientis hydrocodone or a salt or solvate thereof.
 17. The dosage formaccording to claim 14, wherein the active ingredient is morphine or asalt or solvate thereof.
 18. The dosage form according to claim 14,wherein said threads remain substantially coherent and visible to thenaked eye in said further quantity of water for at least one minute. 19.The dosage form according to claim 14, wherein said threads remainsubstantially coherent and visible to the naked eye in said furtherquantity of water for at least ten minutes.
 20. The dosage formaccording to claim 14, comprising at least one active ingredient incontrolled release form.
 21. The dosage form according to claim 14,which further comprises microcrystalline cellulose.
 22. The dosage formaccording to claim 14, which further compriseshydroxypropylmethylcellulose.
 23. A solid dosage form for oraladministration with reduced potential for parenteral abuse, said dosageform comprising: (a) one or more active ingredients with potential forabuse selected from the group consisting of hydrocodone, morphine,oxycodone, tramadol and pharmaceutically acceptable salts and/orsolvates thereof; and (b) one or more viscosity-increasing agents;wherein the dosage form when its total content is comminuted andcombined with 10 ml of water at 25° C. forms an injectable gel that canbe drawn up into and injected back out of a syringe having a diameter of0.9 mm, but wherein the injectable gel cannot be safely injected fromsaid syringe into a blood vessel of an abuser because the presence ofthe injectable gel in the abuser's blood vessels would probably obstructone or more of said abuser's blood vessels.
 24. The dosage formaccording to claim 23, wherein the active ingredient is oxycodone or asalt or solvate thereof.
 25. The dosage form according to claim 23,wherein the active ingredient is hydrocodone or a salt or solvatethereof.
 26. The dosage form according to claim 23, wherein the activeingredient is morphine or a salt or solvate thereof.
 27. The dosage formaccording to claim 23, which further comprises microcrystallinecellulose.
 28. The dosage form according to claim 23, which furthercomprises hydroxypropylmethylcellulose.
 29. The dosage form according toclaim 23, comprising at least one active ingredient in controlledrelease form.